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Nlrp3 inhibitors

A technology of R12, C1-C3, applied in the field of NLRP3 inhibitors, can solve the problem of limited efficacy and non-specificity

Pending Publication Date: 2021-07-23
INFLAZOME LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited efficacy and are nonspecific. Heterosexual

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1253] Example 1: 5-fluoro-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)-7-isopropyl-3,3-dimethyl-2,3- Dihydro-1H-indene-1-carboxamide

[1254]

[1255] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (36 mg, 0.16 mmol) and 5-fluoro-7-isopropyl-3,3-dimethyl -2,3-Dihydro-1H-indene-1-carboxylic acid (Intermediate R7, Step B) (39 mg, 0.16 mmol) was stirred in DCM (6 mL). EDC (60 mg, 0.31 mmol) and DMAP (38 mg, 0.31 mmol) were added to the reaction mixture. The mixture was stirred at room temperature overnight, diluted with DCM (5 mL), and washed with 1M aqueous HCl (3 mL). Concentrate the organic phase. The residue was dissolved in DMSO (0.5 mL), and KO was added t Bu (52 mg, 0.47 mmol). The mixture was purified by reverse phase preparative HPLC method 2 to afford the title compound (12 mg, 17%) as a white solid.

[1256] 1 H NMR (300MHz, methanol-d 4 )δ7.95(d,1H),7.36(s,1H),7.31(d,1H),6.69–6.60(m,1H),6.60–6.51(m,1H),3.96(s,1H),2.71 (s,...

Embodiment 2

[1258] Example 2: 2-(4-fluoro-2,6-diisopropylphenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide potassium salt

[1259]

[1260] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (50 mg, 0.17 mmol) and 2-(4-fluoro-2,6-diisopropylphenyl ) Acetic acid (Intermediate R11) (42 mg, 0.17 mmol) was stirred in DCM (6 mL). EDC (67 mg, 0.35 mmol) and DMAP (43 mg, 0.35 mmol) were added to the reaction mixture. The mixture was stirred overnight, diluted with DCM (5 mL), and washed with 1M aq. HCl (mL). Concentrate the organic phase. The residue was dissolved in DMSO (0.5 mL), and KO was added t Bu (59 mg, 0.52 mmol). The mixture was purified by reverse phase preparative HPLC method 2 to afford the title compound (41 mg, 52%) as a white solid.

[1261] 1 H NMR (300MHz, methanol-d 4 )δ7.90(d,1H),7.34(d,1H),7.28(dd,1H),6.69(d,2H),3.64(s,2H),3.19–2.98(m,2H),2.68(s ,3H), 1.48(d,6H), 1.07(d,12H).

[1262] LCMS: m / z 450 (M+H) + (ES + );448(M...

Embodiment 3

[1263] Example 3: 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2- Methylphenyl)sulfonyl)propionamide

[1264]

[1265] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate L1) (85 mg, 0.37 mmol) and Et 3 N (38 mg, 0.37 mmol) was stirred in DCM (6 mL). Then 3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)propionyl chloride (Intermediate R5) (63 mg, 0.19 mmol) in DCM was added dropwise (1 mL) and stirred overnight. EDC (36 mg, 0.19 mmol) and DMAP (23 mg, 0.35 mmol) were added to the reaction mixture. The mixture was stirred overnight, diluted with DCM (5 mL), and washed with 1M aqueous HCl (3 mL). Concentrate the organic phase. The residue was dissolved in DMSO (0.5 mL) and purified by reverse phase preparative HPLC method 2 to afford the title compound (22 mg, 22%) as a white solid.

[1266] 1 H NMR (300MHz, methanol-d 4 )δ8.14–8.09(m,1H),7.87(d,1H),7.34(d,2H),7.10–7.00(m,1H),6.83(dd,1H),6.72–6.61(m,2H) ...

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Abstract

The present application relates to compounds with NLRP3 inhibitory activity and to associated salts, solvates, prodrugs and pharmaceutical compositions. The present application further relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.

Description

technical field [0001] The present invention relates to compounds having NLRP3 inhibitory activity and related salts, solvates, prodrugs and pharmaceutical compositions. The present invention also relates to the use of such compounds in the treatment and prevention of medical conditions and diseases, most especially by NLRP3 inhibition. Background technique [0002] The NOD-like receptor (NLR) family, the pyrin domain-containing protein 3 (NLRP3) inflammasome, is a component of the inflammatory process, and its aberrant activity is associated with genetic disorders such as cold pyrin-associated periodic It is pathogenic in cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. [0003] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to an apoptosis-associated speck-like protei...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/00A61P9/00A61P11/00A61P25/00A61P29/00A61K31/4545A61K31/341A61P31/00A61P35/00A61P37/00C07D213/64C07D231/18C07D249/04C07D249/12C07D277/36C07D307/64C07D333/34C07D401/12C07D403/12C07D405/12C07D409/12C07D413/12A61K31/4412A61K31/4436A61K31/415A61K31/381A61K31/4192C07D403/06A61K31/4439A61K31/4427A61K31/426A61K31/4196A61K31/4155
CPCC07C2602/08C07C311/51C07C311/54C07C2603/10C07C307/02C07D213/64C07D409/12C07D231/18C07D333/34C07D401/12C07D277/36C07D403/12C07D249/12C07D249/04C07D405/12C07D413/12C07D307/64A61P35/00A61P29/00A61P37/00A61P31/00A61P25/00A61P3/00A61P9/00A61P11/00C07D403/06C07B2200/05
Inventor M·库珀D·米勒A·麦克劳德J·香农S·汤姆I·斯特鲁特D·卡斯塔尼亚J·卡里略阿雷古伊J·范威尔滕堡
Owner INFLAZOME LTD
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